Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway

Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by alpha-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas alpha-synuclein has been genetically linked to the disease process, the pathological relevance of alpha-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of alpha-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for alpha-synuclein. Here, we asked if modulation of ALP affects alpha-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for alpha-synuclein aggregation. ALP inhibition using bafilomycin A(1) (BafA1) significantly potentiates toxicity of aggregated alpha-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of alpha-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for alpha-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.